Substituted quinolinecarboxamides as antiviral agents

ABSTRACT

The present invention discloses disubstiuted 4-oxo-1,4-dihydro-3-quinolinecarboxamide derivatives. The compounds are useful as antiviral agents, in particular, as agents against viruses of the herpes family.

This application is a divisional of U.S. Ser. No. 10/084,015, filed Feb.27, 2002 now U.S. Pat. No. 6,544,990 which claims the benefit of U.S.Serial No. 60/272,607, filed Mar. 1, 2001, under 35 USC 119(e)(i),incorporated herein, by reference in their entirety.

FIELD OF THE INVENTION

The present invention discloses disubstiuted4-oxo-1,4-dihydro-3-quinolinecarboxamide derivatives, and morespecifically, provides compounds of formula (I) described herein below.These compounds are useful as antiviral agents, in particular, as agentsagainst viruses of the herpes family.

BACKGROUND OF THE INVENTION

The herpesviruses comprise a large family of double stranded DNAviruses. They are also a source of the most common viral illnesses inman. Eight of the herpes viruses, herpes simplex virus types 1 and 2(HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus(HCMV), epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8(HHV-6, HHV-7, and HHV-8), have been shown to infect humans.

HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals,respectively. They also occasionally cause infections of the eye andencephalitis. HCMV causes birth defects in infants and a variety ofdiseases in immunocompromised patients such as retinitis, pneumonia, andgastrointestinal disease. VZV is the causitive agent of chicken pox andshingles. EBV causes infectious mononucleosis. It can also causelymphomas in immunocompromised patients and has been associated withBurkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkins disease.HHV-6 is the causative agent of roseola and may be associated withmultiple sclerosis and chronic fatigue syndrome. HHV-7 diseaseassociation is unclear, but it may be involved in some cases of roseola.HHV-8 has been associated with Karposi's sarcoma, body cavity basedlymphomas, and multiple myeloma.

Due to the selective substitutents, Y and Z, on the quinoline ring, andthe unique position of the X substitutent on the N-phenylmethyl offormula I described herein below, compounds of the present inventiondemonstrate unexpected activity against the above reference herpesviralinfections, particularly, human cytomegaloviral infection.

INFORMATION DISCLOSURE

U.S. Pat. No. 5,891,878 discloses the use of compounds of the followingstructure for the treatment of a disease state capable of beingmodulated by inhibition of production of phosphodiesterase IV or tumornecrosis factor,

PCT publication, WO99/32450 discloses compounds of the structure below

which are useful as antiviral agents.

PCT publication, WO00/40561 discloses the quinolinecarboxamide structurebelow as antiviral agents:

PCT publication, WO00/40563 discloses the4-oxo-1,4-dihydro-3-uqinolinecarboxamide structure below as antiviralagents:

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I

or a pharmaceutically acceptable salt thereof wherein

X is Cl, Br, CN, NO₂, or F;

Y is morpholinylmethyl, tetrahydro-2H-pyranylmethyl, hydroxypropynyl, orhydroxypropyl;

Z is het¹, or C₁₋₇alkyl optionally substituted with at least one halo,NR₁R₂, OR³, or het²;

R¹ and R² are independently H, C₁₋₇alkyl, or C₂₋₇alkyl substituted withat least one OH;

R³ is H, or C₁₋₇alkyl;

het¹ is a five-(5), or six-(6) membered saturated or unsaturatedheterocyclic ring bonded via a carbon atom having 1, 2, or 3 heteroatomsselected from the group consisting of oxygen, sulfur, or nitrogen,wherein the het is optionally fused to a benzene ring, and optionallysubstituted with one or more substituents selected from the groupconsisting of halo, OR³, CN, phenyl, C₂R³, CF₃, or C₁₋₆ alkyl which maybe further substituted by one to three SR³, NR³R³, OR³, or CO₂R³ groups;and het² is a five-(5), or six-(6) membered saturated or unsaturatedheterocyclic ring having 1, 2, or 3 heteroatoms selected from the groupconsisting of oxygen, sulfur, or nitrogen, wherein het is optionallyfused to a benzene ring, and optionally substituted with one or moresubstituents selected from the group consisting of halo, OR³, CN,phenyl, CO₂R³, CF₃, oxo, oxime, or C₁₋₆ alkyl which may be furthersubstituted by one to three SR³, NR³R³, OR³, or CO₂R³ groups.

In another aspect, the present invention also provides:

A pharmaceutical composition which comprises a pharmaceuticallyacceptable carrier and an effective amount of a compound of formula I,

a method of treating and preventing herpesviral infections in a mammal,including human, and a method for inhibiting a viral DNA polymerase,comprising contacting the polymerase with an effective inhibitory amountof a compound of claim 1, or a pharmaceutically acceptable salt thereof,

a compound of formula I or a pharmaceutically acceptable salt thereoffor use in medical treatment or prevention of a herpesviral infection ina mammal.

The invention also provides novel intermediates and processes disclosedherein that are useful for preparing compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of the present invention, the carbon atom content ofvarious hydrocarbon-containing moieties is indicated by a prefixdesignating the minimum and maximum number of carbon atoms in themoiety, i.e., the prefix C_(i-j) indicates a moiety of the integer “i”to the integer “j” carbon atoms, inclusive. Thus, for example,(C₁₋₇)alkyl refers to alkyl of one to seven carbon atoms, inclusive, ormethyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl, straight andbranched forms thereof.

The term “het¹” is a five-(5), or six-(6) membered saturated orunsaturated heterocyclic ring bonded via a carbon atom having 1, 2, or 3heteroatoms selected from the group consisting of oxygen, sulfur, ornitrogen, wherein the het is optionally fused to a benzene ring, andoptionally substituted with one or more substituents selected from thegroup consisting of halo, OH, CN, phenyl, CO₂R³, CF₃, OC₁₋₆alkyl, orC₁₋₆ alkyl which may be further substituted by one to three SR³, NR³R³,OR³, or CO₂R³ groups.

The term “het²” is a five-(5), or six-(6) membered saturated orunsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selectedfrom the group consisting of oxygen, sulfur, or nitrogen, wherein het isoptionally fused to a benzene ring, and optionally substituted with oneor more substituents selected from the group consisting of halo, OH, CN,phenyl, CO₂R³, CF₃, OC₁₋₆alkyl, oxo, oxime, or C₁₋₆alkyl which may befurther substituted by one to three SR³, NR³R³, OR³, or CO₂R³ groups.The preferred substitutent is oxo or hydroxy.

When a het contains a sulfur atom, the sulfur atom may be mono- ordi-oxidized.

Examples of“het¹” include, but not limit to, pyridine, imidazole,thiazole, oxazole, thiadiazole, oxadiazole, imidazoline, pyrimidine,pyrazine, or indole.

Examples “het²” include, but not limit to, imidazolidine, imidazoline,pyrazolidine, pyrazoline, dioxolane, imidazole, oxathiolane,oxazolidine, pyrrolidine, pyrroline, piperidine, piperazine, morpholine,thiomorpholine, isochroman, chroman, indoline, or isoindoline.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, tautomeric, orstereoisomeric form, or mixture thereof, of a compound of the invention,which possesses the useful properties described herein, it being wellknown in the art how to prepare optically active forms (for example, byresolution of the racemic form by recrystallization techniques, bysynthesis from optically-active starting materials, by chiral synthesis,or by chromatographic separation using a chiral stationary phase) andhow to determine antiviral activity using the standard tests describedherein, or using other similar tests which are well known in the art.

The compounds of the present invention are generally named according tothe IUPAC or CAS nomenclature system. “Pharmaceutically acceptablesalts” refers to those salts which possess the biological effectivenessand properties of the parent compound and which are not biologically orotherwise undesirable.

Mammal refers to human and animals.

“Optionally” or “may be” means that the subsequently described event orcircumstance may, but need not, occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not.

A “pharmaceutically acceptable carrier” means a carrier that is usefulin preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes a carrier that is acceptable for veterinary use as well ashuman pharmaceutical use. “A pharmaceutically acceptable carrier” asused in the specification and claims includes both one and more than onesuch carrier.

Specifically, X is chloro.

Specifically, Z is C1-7alkyl optionally substituted with one or two OR3.

Specifically, Z is methyl, ethyl or propyl substituted with one or twoOH.

Specifically, Z is methyl, ethyl or propyl substituted with NR1 R2wherein R1 and R2 are independently H, C1-4alkyl, or C2-6alkylsubstituted with one or two OH;

Specifically, Z is methyl or ethyl substituted with N(CH3)2.

Specifically, Z is methyl or ethyl substituted with het2.

Specifically, het1 is pyridine, imidazole, thiazole, oxazole,thiadiazole, oxadiazole, imidazole, pyrimidine, pyrazine, or indole.

Specifically, het2 is 2-oxo-1,3-oxazolidin-4-yl.

Specifically, het2 is 1,1-dioxido-4-thiomorpholinyl.

Specifically, Y is 4-morpholinylmethyl.

Specifically, Y is tetrahydro-2H-pyran-4-ylmethyl.

Specifically, Y is 3-hydroxy-1-propynyl, or 3-hydroxypropyl.

Examples of the present invention are:

(1)N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide,

(2)N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide,

(3)N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propynyl]-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide,

(4)N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,

(5)N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,

(6)N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,

(7)N-(4-chlorobenzyl)-8-[(3S)-3-hydroxy-1-butynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,

(8)N-(4-chlorobenzyl)-8-[(3R)-3-hydroxy-1-butynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,

(9)N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]-1-butynyl}-1,4-dihydro-3-quinolinecarboxamide,

(10)N-(4-chlorobenzyl)-8-(5-hydroxy-1-pentynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,

(11)N-(4-chlorobenzyl)-8-[3-(1,1-dioxido-4-thiomorpholinyl)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,

(12)N-(4-chlorobenzyl)-1-methyl-8-[3-(5-methyl-1H-imidazol-1-yl)prop-1-ynyl]-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(13)N-(4-chlorobenzyl)-8-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(14)N-(4-chlorobenzyl)-8-(3-fluoroprop-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(15)N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-2-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,

(16)N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-3-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,

(17)N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-4-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,

(18)N-(4-chlorobenzyl)-8-(4-hydroxypent-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(19)N-(4-chlorobenzyl)-8-[3-(4-hydroxypiperidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(20)N-(4-chlorobenzyl)-8-[3-(3-hydroxypyrrolidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(21)N-(4-chlorobenzyl)-8-{3-[(2,3-dihydroxypropyl)(methyl)amino]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(22)N-(4-chlorobenzyl)-8-{3-[(2-hydroxyethyl)(methyl)amino]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(23)N-(4-chlorobenzyl)-8-[3-(1H-imidazol-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(24)N-(4-chlorobenzyl)-8-[5-hydroxy-4-(hydroxymethyl)pent-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(25)N-(4-chlorobenzyl)-8-{3-[3-(hydroxymethyl)piperidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(26)N-(4-chlorobenzyl)-8-{3-[4-(2-hydroxyethyl)piperazin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(27)N-(4-chlorobenzyl)-8-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(28)N-(4-chlorobenzyl)-8-[3-(3-hydroxypiperidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(29)N-(4-chlorobenzyl)-8-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(30)N-(4-chlorobenzyl)-8-{3-[2-(2-hydroxyethyl)piperidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(31)8-{3-[butyl(2-hydroxyethyl)amino]prop-1-ynyl}-N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.

The examples of the preferred compounds of the present invention are:

(1)N-(4-chlorobenzyl)-8-(4-hydroxybut-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(2)N-(4-chlorobenzyl)-8-[3-(1,1-dioxidothiomorpholin-4-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(3)N-(4-chlorobenzyl)-1-methyl-8-[3-(5-methyl-1H-imidazol-1-yl)prop-1-ynyl]-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(4)N-(4-chlorobenzyl)-8-(4-hydroxypent-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(5)N-(4-chlorobenzyl)-8-(4-hydroxybut-1-ynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydroquinoline-3-carboxamide,

(6)N-(4-chlorobenzyl)-8-[3-(dimethylamino)prop-1-ynyl]-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydroquinoline-3-carboxamide,

(7)N-(4-chlorobenzyl)-8-[(3R)-3-hydroxybut-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(8)N-(4-chlorobenzyl)-8-[3-(dimethylamino)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(9)N-(4-chlorobenzyl)-8-[(3S)-3-hydroxybut-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(10)N-(4-chlorobenzyl)-8-[5-hydroxy-4-(hydroxymethyl)pent-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(11)N-(4-chlorobenzyl)-8-{3-[4-(2-hydroxyethyl)piperazin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(12)N-(4-chlorobenzyl)-8-[3-(1H-imidazol-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(13)N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-3-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,

(14)N-(4-chlorobenzyl)-8-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(15)N-(4-chlorobenzyl)-8-(5-hydroxypent-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(16)N-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydroquinoline-3-carboxamide,

(17)N-(4-chlorobenzyl)-8-{3-[2-(2-hydroxyethyl)piperidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(18)N-(4-chlorobenzyl)-8-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(19)N-(4-chlorobenzyl)-8-{3-[3-(hydroxymethyl)piperidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(20)N-(4-chlorobenzyl)-8-{3-[(2,3-dihydroxypropyl)(methyl)amino]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(21)N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-4-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,

(22)N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]but-1-ynyl}-1,4-dihydroquinoline-3-carboxamide,

(23)N-(4-chlorobenzyl)-8-[3-(3-hydroxypyrrolidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(24)N-(4-chlorobenzyl)-8-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(25)N-(4-chlorobenzyl)-8-(3-fluoroprop-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide,

(26)N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-2-ylethynyl)-1,4-dihydroquinoline-3-carboxamide,

(27)N-(4-chlorobenzyl)-8-[3-(3-hydroxypiperidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.

The following Schemes A-G describe the preparation of the compounds offormula I of the present invention. All of the starting materials areprepared by procedures described in these schemes, by procedures wellknown to one of ordinary skill in organic chemistry or can be obtainedcommercially. All of the final compounds of the present invention areprepared by procedures described in these schemes or by proceduresanalogous thereto, which would be well known to one of ordinary skill inorganic chemistry. All of the variables used in the schemes are asdefined below or as in the claims.

Scheme A illustrates the preparation of the precursors to compounds offormula I wherein Y is tetrahydropyranylmethyl.

As shown in Scheme A, treatment of 4-nitrobenzylbromide withtriphenylphosphine provides the phosphonium salt A-2 which undergoes aWittig reaction with tetrahydrapyran-4-one to give the nitrobenzylidineA-3. Reduction provides the tetrahydropyranylmethylaniline A-4 which canbe condensed with diethyl ethoxymethylenemalonate and cyclized to givethe quinoline A-6. Treatment with an amine such as 4-chlorobenzylamineat elevated temperatures gives the corresponding amide A-7. Alkylationof the N-1 nitrogen by treatment with potassium or cesium carbonate andan alkylating agent such as methyl iodide provides theN-methyl-oxo-dihydroquinoline A-8.

Scheme B illustrates the preparation of the precursors to compounds offormula I wherein Y is morpholinylmethyl.

As shown in Scheme B, iodination of ethyl aminobenzoate withN-iodosuccinimide followed by reduction of the ester withdiisobutylaluminium hydride or superhydride provides the hydroxymethylaniline B-3. Condensation with diethyl ethoxymethylenemalonate followedby protection of the hydroxymethyl group as the corresponding acetateand thermal cyclization provides the quinoline carboxylic ester B-6.Treatment with an amine such as 4-chlorobenzyl amine at elevatedtemperature results in deprotection of the acetate and conversion to thecorresponding amide B-7. Alkylation of the N-1 nitrogen by treatmentwith an alkylating agent such as methyl iodide in the presence of a basesuch as potassium or cesium carbonate gives the 4-oxo-dihydroquinolineB-8. Conversion of the hydroxymethyl group to a chloromethyl group bytreatment with MsCl in collidine followed by displacement of thechloride with an amine (such as morpholine) provides themorpholinylmethyl quinolone B-10.

Scheme C illustrates the preparation of the precursors to compounds offormula I wherein Y is 3-hydroxypropynyl.

As shown in Scheme C, palladium-catalyzed coupling of the iodoanilineC-1 with an acetylene such as propargyl alcohol followed by iodinationwith an iodinating agent such as ICI provides the iodoaniline C-3.Condensation with diethyl ethoxymethylenemalonate and cyclization eitherunder thermal conditions provides the quinoline carboxylic ester C-4.Treatment of the ester with an amine such as 4-chlorobenzylamine atelevated temperature and subsequent alkylation of the N-1 nitrogen as inthe previous charts provides the3-hydroxypropynyl-4-oxo-dihydroquinoline C-6.

Scheme D illustrates the preparation of the precursors to compounds offormula I wherein Y is 3-hydroxypropropyl.

As shown in Scheme D, hydrogenation of the acetylene C-2 with anappropriate catalyst such as palladium on carbon and subsequentiodination with an iodinating agent such as N-iodosuccinimide or ICIprovides the 2-iodo-3-hydroxypropylaniline D-2. Condensation of theaniline with diethyl ethoxymethylenemalonate, protection of the alcoholas the corresponding acetate and cyclization under thermal conditionsprovides the quinoline carboxylic ester D-3. Treatment of the ester withan amine such as 4-chlorobenzylamine results in both conversion to thecorresponding amide and deprotection of the acetate group to give D-4.Alkylation of the N-1 nitrogen by treatment with an alkylating agentsuch as methyl iodide in the presence of a base such as potassium orcesium carbonate provides the6-(3-hydroxypropyl)-8-iodo-4-oxo-dihydroquinoline D-5.

Alternatively, many of the above quinolines can be prepared startingwith anilines which already incorporate the N-1 alkyl group as shown inScheme E. In these cases, conversion of the aniline to the correspondingquinoline E-2 can be accomplished by condensation with diethylethoxymethylenemalonate and subsequent cyclization by treatment withEaton's reagent. Conversion to the corresponding amide can beaccomplished in several ways including treatment of the ester with anappropriate amine such as 4-chlorobenzylamine at elevated temperaturesor saponification to the acid, activation of the acid and coupling withthe desired amine. The requisite N-alkyl anilines can be prepared in ananalogous manner as the anilines described above.

The precursors described above can undergo Sonogashira couplings(PdCl2(PPh3)2, CuI, Et2NH) with substituted acetylenes to provide thedesired compounds as shown in Scheme F.

As shown in Scheme G, the starting material G-0, whose preparation isdescribed Scheme as B-10 (wherein X is chloro), is reacted withpropargyl alcohol under palladium catalyzed conditions to afford thecompound of formula G-1[N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide].The alcohol of compound G-1 is converted to a leaving group and isdisplaced by various het to afford compounds of formula G-2.Alternatively, the alcohol of the compound of formula G-1 is convertedto a leaving group and is reacted with amines to afford compounds offormula G-3.

It will be apparent to those skilled in the art that the describedsynthetic procedures are merely representative in nature and alternativesynthetic processes are known to one of ordinary skill in organicchemistry.

The compounds of the present invention and pharmaceutically acceptablesalts thereof are useful as antiviral agents. Thus, these compounds areuseful to combat to viral infections in mammals. Specifically, thesecompounds have anti-viral activity against the herpes virus,cytomegalovirus (CMV). These compounds are also active against otherherpes viruses, such as the varicella zoster virus, the Epstein-Barrvirus, the herpes simplex virus, and the human herpes virus type 8(HHV-8).

The compounds of the present invention may also useful for the treatmentof several cardiovascular diseases such as atherosclerosis andrestenosis. These diseases have been implicated connecting withinflammation of coronary vessel walls resulting from infection orreactivation of herpesviruses.

The compounds of the present invention may also be useful for thetreatment of herpesvirus infections in animals, for example, illnessescaused by bovine herpesvirus 1-5 (BHV), ovine herpesvirus 1 and 2,Canine herpesvirus 1 equine herpesvirus 1-8 (EHV), feline herpesvirus 1(FHV), and pseudorabies virus (PRV).

Pharmaceutical Salts

The compound of formula I may be used in its native form or as a salt.In cases where forming a stable nontoxic salt is desired, administrationof the compound as a pharmaceutically acceptable salt may beappropriate. Examples of pharmaceutically acceptable salts are organicacid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,ketoglutarate, and glycerophosphate. Suitable inorganic salts may alsobe formed, including hydrochloride, hydrobromide, sulfate, nitrate,bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a compound ofthe invention with a suitable acid affording a physiologicallyacceptable anion.

Routes of Administration

In therapeutic use for treating, or combating, viral infections in amammal (i.e. human and animals) a compound of the present invention, itspharmaceutical compositions and other antiviral agents can beadministered orally, parenterally, topically, rectally, transmucosally,or intestinally.

Parenteral administrations include indirect injections to generate asystemic effect or direct injections to the afflicted area. Examples ofparenteral administrations are subcutaneous, intravenous, intramuscular,intradermal, intrathecal, intraocular, intranasal, intravetricularinjections or infusions techniques.

Topical administrations include the treatment of infectious areas ororgans readily accessibly by local application, such as, for example,eyes, ears including external and middle ear infections, vaginal, openwound, skins including the surface skin and the underneath dermalstructures, or other lower intestinal tract. It also includestransdermal delivery to generate a systemic effect.

The rectal administration includes the form of suppositories.

The transmucosal administration includes nasal aerosol or inhalationapplications.

The preferred routes of administration are oral and parenteral.

Composition/Formulation

Pharmaceutical compositions of the present invention may be manufacturedby processes well known in the art, e.g., by means of conventionalmixing, dissolving, granulation, dragee-making, levigating, emulsifying,encapsulating, entrapping, lyophilizing processes or spray drying.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For oral administration, the compounds can be formulated by combiningthe active compounds with pharmaceutically acceptable carriers wellknown in the art. Such carriers enable the compounds of the invention tobe formulated as tablets, pills, lozenges, dragees, capsules, liquids,solutions, emulsions, gels, syrups, slurries, suspensions and the like,for oral ingestion by a patient. A carrier can be at least one substancewhich may also function as a diluent, flavoring agent, solubilizer,lubricant, suspending agent, binder, tablet disintegrating agent, andencapsulating agent. Examples of such carriers or excipients include,but are not limited to, magnesium carbonate, magnesium stearate, talc,sugar, lactose, sucrose, pectin, dextrin, mannitol, sorbitol, starches,gelatin, cellulosic materials, low melting wax, cocoa butter or powder,polymers such as polyethylene glycols and other pharmaceuticalacceptable materials.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with a fillersuch as lactose, a binder such as starch, and/or a lubricant such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, liquid polyethyleneglycols, cremophor, capmul, medium or long chain mono-, di- ortriglycerides. Stabilizers may be added in these formulations, also.

Liquid form compositions include solutions, suspensions and emulsions.For example, there may be provided solutions of the compounds of thisinvention dissolved in water and water-propylene glycol andwater-polyethylene glycol systems, optionally containing suitableconventional coloring agents, flavoring agents, stabilizers andthickening agents.

The compounds may also be formulated for parenteral administration,e.g., by injection, bolus injection or continuous infusion. Formulationsfor parenteral administration may be presented in unit dosage form,e.g., in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulating materials such as suspending, stabilizing and/or dispersingagents.

For injection, the compounds of the invention may be formulated inaqueous solution, preferably in physiologically compatible buffers orphysiological saline buffer. Suitable buffering agents include trisodiumorthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine,L(+)-lysine and L(+)-arginine.

Parenteral administrations also include aqueous solutions of a watersoluble form, such as, without limitation, a salt, of the activecompound. Additionally, suspensions of the active compounds may beprepared in a lipophilic vehicle. Suitable lipophilic vehicles includefatty oils such as sesame oil, synthetic fatty acid esters such as ethyloleate and triglycerides, or materials such as liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers and/or agents that increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water,before use. For suppository administration, the compounds may also beformulated by mixing the agent with a suitable non-irritating excipientwhich is solid at room temperature but liquid at rectal temperature andtherefore will melt in the rectum to release the drug. Such materialsinclude cocoa butter, beeswax and other glycerides.

For administration by inhalation, compounds of the present invention canbe conveniently delivered through an aerosol spray in the form ofsolution, dry powder, or suspensions. The aerosol may use a pressurizedpack or a nebulizer and a suitable propellant. In the case of apressurized aerosol, the dosage unit may be controlled by providing avalve to deliver a metered amount. Capsules and cartridges of, forexample, gelatin for use in an inhaler may be formulated containing apower base such as lactose or starch.

For topical applications, the pharmaceutical composition may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion such as suspensions, emulsion, or cream containingthe active components suspended or dissolved in one or morepharmaceutically acceptable carriers. Suitable carriers include, but arenot limited to, mineral oil, sorbitan monostearate, polysorbate 60,cetyl esters wax, ceteary alcohol, 2-octyldodecanol, benzyl alcohol andwater.

For ophthalmic and otitis uses, the pharmaceutical compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or preferably, as solutions in isotonic, pH adjusted sterilesaline, either with or without a preservative such as a benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticalcompositions may be formulated in an ointment such as petrolatum.

In addition to the formulations described previously, the compounds mayalso be formulated as depot preparations. Such long acting formulationsmay be in the form of implants. A compound of this invention may beformulated for this route of administration with suitable polymers,hydrophobic materials, or as a sparing soluble derivative such as,without limitation, a sparingly soluble salt.

Additionally, the compounds may be delivered using a sustained-releasesystem. Various sustained-release materials have been established andare well known by those skilled in the art. Sustained-release capsulesmay, depending on their chemical nature, release the compounds for 24hours or for up to several days.

Dosage

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in anamount sufficient to achieve the intended purpose, i.e., the treatmentor prevention of infectious diseases. More specifically, atherapeutically effective amount means an amount of compound effectiveto prevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

The quantity of active component, that is the compound of thisinvention, in the pharmaceutical composition and unit dosage formthereof may be varied or adjusted widely depending upon the manner ofadministration, the potency of the particular compound and the desiredconcentration. Determination of a therapeutically effective amount iswell within the capability of those skilled in the art. Generally, thequantity of active component will range between 0.5% to 90% by weight ofthe composition.

Generally, an antiviral effective amount of dosage of active componentwill be in the range of about 0.1 to about 400 mg/kg of body weight/day,more preferably about 1.0 to about 50 mg/kg of body weight/day. It is tobe understood that the dosages may vary depending upon the requirementsof each subject and the severity of the viral infection being treated.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

Also, it is to be understood that the initial dosage administered may beincreased beyond the above upper level in order to rapidly achieve thedesired plasma concentration. On the other hand, the initial dosage maybe smaller than the optimum and the daily dosage may be progressivelyincreased during the course of treatment depending on the particularsituation. If desired, the daily dose may also be divided into multipledoses for administration, e.g., two to four times per day.

In cases of local administration or selective uptake, the effectivelocal concentration of the drug may not be related to plasmaconcentration and other procedures know in the art may be used todetermine the desired dosage amount.

Biological Data

While many of the compounds of the present invention have shown activityagainst the CMV polymerase, these compounds may be active against thecytomegalovirus by this or other mechanisms of action. Thus, thedescription below of these compounds' activity against the CMVpolymerase is not meant to limit the present invention to a specificmechanism of action.

The compounds of the present invention have shown activity in one ormore of the assays described below. All of these assays are indicativeof a compound's activity and thus of its use as an anti-viral agent.

The HCMV polymerase assay is performed using a scintillation proximityassay (SPA) as described in several references, such as N. D. Cook, etal., Pharmaceutical Manufacturing International, pages 49-53 (1992); K.Takeuchi, Laboratory Practice, September issue (1992); U.S. Pat. No.4,568,649 (1986); which are incorporated by reference herein. Reactionsare performed in 96-well plates. The assay is conducted in 100 μl volumewith 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl2, 0.36 mg/ml BSA,and 90 nM 3H-dTTP. Assays are run with and without CHAPS,(3-[(3-Cholamidopropyl)-dimethylammonio]-1-propane-sulfonate) at a finalconcentration of 2 mM. HCMV polymerase is diluted in enzyme dilutionbuffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100μg/ml BSA, and 0.01% sodium azide. The HCMV polymerase, which isexpressed in recombinant baculovirus-infected SF-9 cells and purifiedaccording to literature procedures, is added at 10% (or 10 μl) of thefinal reaction volume, i.e., 100 μl. Compounds are diluted in 50% DMSOand 10 μl are added to each well. Control wells contain an equivalentconcentration of DMSO. Unless noted otherwise, reactions are initiatedvia the addition of 6 nM biotinylated poly(dA)-oligo(dT) template/primerto reaction mixtures containing the enzyme, substrate, and compounds ofinterest. Plates are incubated in a 25 C. or 37 C. H2O bath andterminated via the addition of 40 μl/reaction of 0.5 M EDTA (pH 8) perwell. Reactions are terminated within the time-frame during whichsubstrate incorporation is linear and varied depending upon the enzymeand conditions used, i.e., 30 min. for HCMV polymerase. Ten μl ofstreptavidin-SPA beads (20 mg/ml in PBS/10% are added followingtermination of the reaction. Plates are incubated 10 min. at 37 C., thenequilibrated to room temperature, and counted on a Packard Topcount.Linear regressions are performed and IC50′s are calculated usingcomputer software.

A modified version of the above HCMV polymerase assay is performed asdescribed above, but with the following changes: Compounds are dilutedin 100% DMSO until final dilution into assay buffer. In the previousassay, compounds are diluted in 50% DMSO. 4.5 mM dithiotherotol (DTT) isadded to the polymerase buffer. Also, a different lot of CMV polymeraseis used, which appears to be more active resulting in a more rapidpolymerase reaction.

Results of the testing of compounds of the present invention in thisassay are shown in Table b 1 below.

All results are listed as Polymerase IC50 (μM) values. In Table 1, theterm “n.d.” refers to activity data not determined.

TABLE 1 Polymerase IC₅₀ (μM) Example number CMV HSV VZV 1 0.32 0.25 0.182 0.32 n.d. n.d. 3 0.87 n.d. n.d. 4 0.83 0.83 0.36 5 1.6 n.d. n.d. 6 0.80.82 0.36 7 0.76 0.45 0.18 8 0.87 1 0.48 9 0.55 n.d. n.d. 10 0.48 0.410.16 11 0.36 0.28 0.18 12 0.77 n.d. n.d. 13 0.50 0.49 0.25 14 0.52 n.d.n.d. 15 0.32 0.26 0.14 16 0.47 0.28 0.15 17 0.42 0.21 0.11 18 0.61 n.d.n.d. 19 1.01 n.d. n.d. 20 1.02 n.d. n.d. 21 0.80 n.d. n.d. 22 0.82 n.d.n.d. 23 0.33 0.22 0.10 24 0.56 n.d. n.d. 25 0.74 n.d. n.d. 26 1.29 n.d.n.d. 27 0.94 n.d. n.d. 28 0.82 n.d. n.d. 29 0.73 n.d. n.d. 30 0.71 n.d.n.d. 31 0.49 0.55 0.33

The compounds and their preparation of the present invention will bebetter understood in connection with the following examples, which areintended as an illustration of and not a limitation upon the scope ofthe invention.

EXAMPLES Preparation 1 (4-nitrobenzyl)(triphenyl)phosphonium Bromide

To a solution of triphenylphosphine (25.92 g) in 300 mL CH2Cl2 is added4-nitrobenzylbromide (31.47 g). The solution is allowed to stirovernight. The mixture is concentrated. The resulting solid istriturated with Et2O, filtered and dried to yield 54.58 g (95%) of thedesired product as a white solid.

Physical characteristics are as follows: 1H NMR (CDCl3) δ 7.81, 7.75,7.61, 7.47, 5.99.

Preparation 2 4-(4-nitrobenzylidene)tetrahydro-2H-pyran

To a 500 mL 3-necked flask is added NaH (2.0 g of a 60% suspension inmineral oil) and 35 mL of DMSO. The resulting solution is heated at 80°C. for 1 h then cooled in an ice-water bath. To this is then added asolution of the phosphonium bromide (23.92 g) in 200 mL warm DMSO. Themixture is stirred at room temperature for 1 h.Tetrahydro-4H-pyran-4-one (4.62 mL) is then added. The mixture isallowed to stir overnight at room temperature and then at 80° C. for 2days. The mixture is poured over ice and extracted with Et2O. Thecombined organic extracts are dried and condensed. Chromatography(Biotage flash 40S, gradient from hexanes to 80% CH2Cl2/hexanes) yields4.83 g (44%) of the desired product as a bright yellow solid.

Physical characteristics are as follows: 1H NMR (CDCl3) δ 8.19, 7.35,6.38, 3.82, 3.70, 2.55, 2.46.

Preparation 3 2-iodo-4-(tetrahydro-2H-pyran-4-ylmethyl)aniline

A mixture of 4-(4-nitrobenzylidene)tetrahydro-2H-pyran (2.0 g) and PtO2(0.2 g) is hydrogenated at 40 p.s.i. H2 for 3.5 h. The mixture isfiltered through celite and the filtrate condensed. The crude residue isdissolved in a mixture of 40 mL CHCl3 and 4 mL MeOH. To this is addedsodium acetate (2.24 g), followed by the dropwise addition of a solutionof ICl (0.69 mL) in MeOH (10 mL). The reaction is stirred at roomtemperature for 1 h then quenched by pouring into an iced saturatedsolution of aqueous sodium bisulfite (200 mL). The mixture is stirredfor 30 minutes then concentrated until all of the organics are gone. Theaqueous solution is extracted with CH2Cl2 (3×). The combined organiclayers are washed with brine, dried and condensed. The crude product ischromatographed (Biotage flash 40M, eluent CH2Cl2) to yield 1.0 g (34%)of the desired product as a yellow oil.

Physical characteristics are as follows: 1H NMR (CDCl3) δ 7.47, 6.95,6.76, 3.95, 3.34, 2.41, 1.68, 1.56, 1.31; OAMS supporting ions at:ESI+318.1.

Preparation 4 Ethyl4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate

A mixture of 2-iodo-4-(tetrahydro-2H-pyran-4-ylmethyl)aniline (1.0 g)and diethyl ethoxymethylenemalonate (0.70 mL) is heated at 130° C. for 1h. The mixture is cooled to room temperature. Diphenyl ether (20 mL) isadded and the reaction is heated to 250° C. for 1 h. The mixture iscooled and the resulting solid is collected and washed with hexanes. Thecrude product is chromatographed (Biotage flash 40M, eluent 2%MeOH/CH2Cl2) to yield 0.80 g (58%) of the desired product as anoff-white solid.

Physical characteristics are as follows: m.p. 218-222° C. (dec); 1H NMR(DMSO-d6) δ 11.18, 8.45, 8.09, 7.95, 4.22, 3.80, 3.22, 2.61, 1.76, 1.45,1.27, 1.20; IR (drift) 3073, 2928, 2918, 1709, 1619, 1600, 1560, 1517,1327, 1292, 1216, 1170, 1154, 1135, 1090 cm−1. OAMS supporting ions at:ESI+442.0 ESI−441.0; HRMS (FAB) calcd for C18H20INO4+H1 442.0517, found442.0526; Anal. calcd for C18H20IN04: C, 48.99; H, 4.57; N, 3.17, found:C, 49.09; H, 4.58; N, 3.24.

Preparation 5N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxamide

A suspension of ethyl4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate(0.8 g) and 4-chlorobenzylamine (1.54 mL) is heated to 180° C. for 1 h.The reaction is cooled to room temperature. The resulting solid iscollected and washed with Et2O. The crude solid is adsorbed onto silicaand chromatographed (Biotage flash 40S, eluent 1% MeOH/CH2Cl2 then 2%MeOH/CH2Cl2). Fractions homogeneous by TLC are combined andconcentrated. The resulting solid is triturated with EtOAc/hexanes toyield 0.73 g (75%) of the desired product as a white solid.

Physical characteristics are as follows: m.p. 257-259° C.; 1H NMR(DMSO-d6) δ 10.39, 8.70, 8.15, 8.04, 7.38, 4.54, 3.80, 3.22, 2.63, 1.79,1.48, 1.24; IR (drift) 2925, 1654, 1596, 1554, 1513, 1493, 1099, 1090,850, 828, 811, 799, 781, 766, 724 cm−1; OAMS supporting ions at:ESI+536.7 ESI−534.7; Anal. calcd for C23H22ClIN2O3: C, 51.46; H, 4.13;N, 5.22, found: C, 51.31; H, 4.13; N, 5.20.

Preparation 6N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide

To a mixture ofN-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxamide(0.075 g) and K2CO3 (0.077 g) in 5 mL DMF is added methyl iodide (2.4 g)and the mixture is stirred at room temperature for 5 days. The mixtureis then poured into water and the resulting solid collected. The crudeproduct is chromatographed (Biotage flash 40S, eluent CH2Cl2 then 1%MeOH/CH2Cl2). Fractions homogeneous by TLC are combined andconcentrated. The resulting solid is recrystallized from CH2Cl2/hexanesto yield 0.037 g (48%) of the desired product as a white solid.

Physical characteristics are as follows: m.p. 175-177° C.; 1H NMR(DMSO-d6) δ 10.21, 8.75, 8.37, 8.16, 7.37, 4.55, 4.38, 3.80, 3.22, 2.62,1.75, 1.45, 1.20; IR (diffuse reflectance) 2926, 1658, 1598, 1575, 1538,1489, 1459, 1360, 1243, 1234, 1134, 1103, 1091, 1015, 808 cm−1; MS (EI)m/z 550 (M+), 550, 410, 384, 383, 257, 142, 142, 140, 115, 55; Anal.calcd for C24H24ClIN203: C, 52.33; H, 4.39; N, 5.09; found: C, 52.09; H,4.36; N, 5.09.

Example 1N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide

To a solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide(0.200 g), PdCl2(PPh3)2 (0.012 g) and CuI (0.029 g) in 10 mL Et2NH and 5mL CH2Cl2 is added propargyl alcohol (0.021 g). The mixture is allowedto stir overnight at room temperature. The solvents are evaporated andthe residue is partitioned between CH2Cl2 and water. The aqueous layeris extracted with CH2Cl2 (3×). The combined organic layers are washedwith brine, dried and condensed. The crude product is chromatographed(Biotage flash 40S, eluent 1% MeOH/CH2Cl2 then 2% MeOH/CH2Cl2).Fractions homogeneous by TLC are combined and concentrated. Theresulting solid is recrystallized from CH2Cl2/Et2O to yield 0.114 g(66%) of the desired product as a white solid.

Physical characteristics are as follows: m.p. 166-168° C.; 1H NMR(DMSO-d6) δ 10.29, 8.74, 8.15, 7.77, 7.38, 5.42, 4.56, 4.42, 4.39, 3.80,3.22, 2.65, 1.77, 1.45, 1.24; IR (diffuse reflectance) 2916, 2850, 1657,1603, 1556, 1489, 1408, 1359, 1244, 1131, 1109, 1088, 1014, 849, 810cm−1; MS (EI) m/z 478 (M+), 338, 312, 311, 226, 140, 125, 89, 77, 56,55; HRMS (FAB) calcd for C27H27ClN2O4+H1 479.1737, found 479.1735; Anal.calcd for C27H27ClN2O4: C, 67.71; H, 5.68; N, 5.85; found: C, 67.31; H,5.73; N, 5.74.

Example 2N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide

A solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide(0.074 g), copper iodide (0.013 g), Pd(PPh3)2Cl2 (0.007 g) and3-butyn-1-ol (0.02 mL) in 7 mL diethylamine is stirred at roomtemperature for 3 days. The reaction is partitioned between CH2Cl2 andH2O. The aqueous is extracted 3×with CH2Cl2. The organics are combined,dried over Na2SO4, filtered and concentrated. The residue is dissolvedin CH2Cl2 and adsorbed onto silica. Purification by Biotage Flash 40Schromatography (eluent CH2Cl2 (1L), 0.5% MeOH/CH2Cl2 (1L), 1%MeOH/CH2Cl2 (1L), 1.5% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3%MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L), 7% MeOH/CH2Cl2 (1L)) affords theproduct as a tan residue. The residue is dissolved in a minimal amountof CH2Cl2 and hexanes are added to affect recrystallization. Thesolution is placed in the freezer for 18 h after which the product iscollected and dried (0.037 g, 57%).

Physical characteristics are as follows: m.p. 186-188° C.; 1H NMR (300MHz, DMSO-d6) δ 10.31, 8.73, 8.13, 7.76, 7.40, 7.36, 4.96, 4.55, 4.43,3.80, 3.64, 3.22, 2.64, 1.77, 1.43, 1.22; IR (drift) 2917, 1656, 1603,1556, 1492, 1446, 1361, 1231, 1127, 1086, 1056, 845, 808, 744, 703 cm−1;MS (FAB) m/z 493, 495, 494, 493, 492, 353, 352, 350, 219, 127, 125.

Example 3N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propynyl]-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide

A solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide(0.070 g), copper iodide (0.013 g), Pd(PPh3)2Cl2 (0.007 g) andN,N-dimethylpropargylamine (0.020 mL) in 7 mL diethylamine is stirred atroom temperature for 3 days. The reaction is partitioned between CH2Cl2and H2O. The aqueous layer is extracted 3×with CH2Cl2. The organics arecombined, dried over Na2SO4, filtered and concentrated. The residue isdissolved in CH2Cl2 and adsorbed onto silica. Purification by BiotageFlash 40S (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L),3% MeOH/CH2Cl2 (1L), 4% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L)) affordsthe product as a tan residue. Recrystallization with CH2Cl2/hexanesaffords the desired product (0.046 g, 70%).

Physical characteristics are as follows: m.p. 157-159° C.; 1H NMR (300MHz, DMSO-d6) δ 8.74, 8.16, 7.81, 7.40, 7.36, 4.56, 4.44, 3.80, 3.57,3.22, 2.66, 2.31, 1.77, 1.45, 1.23; IR (drift) 2916, 2852, 1656, 1604,1552, 1490, 1466, 1448, 1360, 1243, 1133, 1128, 1091, 1014, 808 cm−1; MS(FAB) m/z 506, 509, 508, 507, 506, 505, 504, 365, 338, 125, 58; HRMS(FAB) calcd for C29H32ClN3O3+H 1 506.2210, found 506.2202.

Preparation 7 Ethyl 4-amino-3-iodobenzoate

To a solution of ethyl 4-aminobenzoate (13.0 g) in DMF (33 mL) is addeda solution of N-iodosuccinimide (18.6 g) in DMF (39 mL). The reaction isstirred at room temperature overnight. The mixture is poured into 800 mLwater. The resulting solid is collected and dried to yield 20.7 g (90%)of the titled compound.

Physical characteristics are as follows: m.p. 71-74° C.; 1H NMR (300MHz, DMSO-d6) δ 8.10, 7.65, 6.74, 4.21, 1.27; IR (drift) 3455, 3364,1688, 1615, 1592, 1364, 1324, 1292, 1286, 1249, 1152, 1127, 818, 762,671 cm−1; OAMS supporting ions at: ESI+291.9 ESI−289.9; Anal. calcd forC9H10INO2: C, 37.14; H, 3.46; N, 4.81, found: C, 37.02; H, 3.44; N,4.81.

Preparation 8 (4-amino-3-iodophenyl)methanol

To a solution of ethyl 4-amino-3-iodobenzoate (8.0 g) in CH2Cl2 (56 mL)cooled to 0° C. is added diisobutylaluminum hydride in CH2Cl2 (110 mL ofa 1M solution). The reaction is stirred at 0° C. for 2 h then quenchedby the addition of MeOH (50 mL). To this is added 1N HCl (100 mL). Themixture is concentrated to remove the organics. The aqueous solution isextracted with CH2Cl2 (3×). The combined organic layers are dried overNa2SO4, filtered and condensed. The resulting residue is adsorbed ontosilica and chromatographed (Biotage flash 40M, eluent CH2Cl2 (2L), 1%MeOH/CH2Cl2 (2L), 2% MeOH/CH2Cl2). Fractions homogeneous by TLC arecombined and condensed to afford (4-amino-3-iodophenyl)methanol.

Physical characteristics are as follows: 1H NMR (300 MHz, DMSO-d6) δ7.49, 7.01, 6.70, 6.00, 4.95, 4.28.

Preparation 9 diethyl2-{[4-(hydroxymethyl)-2-iodoanilino]methylene}malonate

A solution of (4-amino-3-iodophenyl)methanol (5.97 g) and diethylethoxymethylenemalonate (5.34 mL) is heated at 100° C. for 30 min. Thereaction is cooled to room temperature. The resulting solid is dissolvedin a mixture of CH2Cl2 and MeOH, adsorbed onto silica andchromatographed (Biotage flash 40M, eluent CH2Cl2 (1L), 0.5% MeOH/CH2Cl2(5L)). Product containing fractions are combined and condensed to afforddiethyl 2-{[4-(hydroxymethyl)-2-iodoanilino]methylene}malonate as awhite solid.

Physical characteristics are as follows: m.p. 152-154° C.; 1H NMR (300MHz, DMSO-d6) δ 11.0, 8.43, 7.83, 7.47, 7.38, 5.29, 4.45, 4.23, 4.14,1.27, 1.25; IR (drift) 1680, 1644, 1593, 1423, 1384, 1373, 1349, 1296,1285, 1267, 1242, 1202, 1036, 1004, 798 cm−1; OAMS supporting ions at:ESI+419.7 ESI−417.8; Anal. calcd for C15H18INO5: C, 42.98; H, 4.33; N,3.34, found: C, 42.73; H, 4.21; N, 3.33.

Preparation 10 diethyl2-({4-[(acetyloxy)methyl]-2-iodoanilino}methylene)malonate

A solution of diethyl2-{[4-(hydroxymethyl)-2-iodoanilino]methylene}malonate (0.20 g) andacetic anhydride (0.054 mL) in acetic acid (0.24 mL) is heated at 80° C.overnight. The reaction is cooled to room temperature and poured into 50mL of water. The resulting solid is filtered and dried to yield 0.19 g(87%) of diethyl2-({4-[(acetyloxy)methyl]-2-iodoanilino}methylene)malonate as a whitesolid.

Physical characteristics are as follows: m.p. 128-131° C.; 1H NMR (300MHz, DMSO-d6) δ 10.99, 8.44, 7.91, 7.51, 7.44, 5.01, 4.24, 4.14, 2.06,1.27, 1.25; IR (drift) 1737, 1686, 1648, 1600, 1428, 1362, 1349, 1299,1267, 1248, 1209, 1039, 1023, 809, 797 cm−1; OAMS supporting ions at:EST+461.7 ESI−459.7; Anal. Calcd for C17H20INO6: C, 44.27; H, 4.37; N,3.04, found: C, 44.39; H, 4.37; N, 3.09.

Preparation 11 ethyl6-[(acetyloxy)methyl]-4-hydroxy-8-iodo-3-quinolinecarboxylate

A solution of diethyl 2-({4-[(acetyloxy)methyl]-2-iodoanilino}methylene)malonate (1.75 g) in Ph2O (20 mL) is heated at 250° C. for 40 min. Thereaction is cooled to room temperature and diluted with hexanes. Theresulting solid is collected and dried. The crude solid is adsorbed ontosilica and chromatographed (Biotage flash 40S, eluent CH2Cl2 (1L), 1%MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L). Product containing fractions arecombined and concentrated to yield 0.98 g (62%) of ethyl6-[(acetyloxy)methyl]-4-hydroxy-8-iodo-3-quinolinecarboxylate.

Physical characteristics are as follows: m.p. 119-123° C.; 1H NMR (300MHz, DMSO-d6) δ 11.29, 8.48, 8.23, 8.16, 5.15, 4.23, 2.09, 1.28; IR(drift) 2993, 2956, 1738, 1711, 1602, 1550, 1524, 1331, 1293, 1284,1242, 1218, 1172,1093, 1035 cm−1; OAMS supporting ions at: ESI+415.8ESI−413.9; HRMS (FAB) calcd for C15H14INO5+H1 415.9997, found 416.0000;Anal. Calcd for C15H14INO5: C, 43.39; H, 3.40; N, 3.37, found: C, 43.55;H, 3.39; N, 3.73.

Preparation 12N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-8-iodo-3-quinolinecarboxamide

A suspension of ethyl6-[(acetyloxy)methyl]-4-hydroxy-8-iodo-3-quinolinecarboxylate (0.90 g)and 4-chlorobenzylamine (2.6 mL) is heated at 180° C. for 1 h. Thereaction is cooled to room temperature and diluted with Et2O. Theresulting solid is filtered and triturated with acetone to yield 0.74 g(73%) ofN-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-8-iodo-3-quinolinecarboxamide.

Physical characteristics are as follows: m.p. 283-286° C.; 1H NMR (300MHz, DMSO-d6) δ 11.61, 10.29, 8.71, 8.23, 7.38, 5.46, 4.60, 4.55; IR(drift) 3369, 3235, 1654, 1598, 1556, 1517, 1491, 1351, 1281, 1213,1181, 1069, 811, 799, 723 cm−1; OAMS supporting ions at: ESI+468.6ESI−466.6; Anal. calcd for C18H14ClIN2O3: C, 46.13; H, 3.01; N, 5.98,found: C, 46.12; H, 2.99; N, 5.99.

Preparation 13N-(4-chlorobenzyl)-6-(hydroxymethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide

A solution ofN-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-8-iodo-3-quinolinecarboxamide(6.5g) in anhydrous DMF (116.7 mL) is heated to 65° C. to solubilize thestarting material. The solution is allowed to cool to room temperature.To this solution is added K2CO3 (7.68 g) and CH3I (8.65 mL). Thereaction is stirred at room temperature overnight. The reaction ispoured into H2O (1L) to precipitate the product. The solid is filtered,adsorbed onto silica, and chromatographed in 2 batches (eluent 100%CH2Cl2 (3L), 0.5% MeOH in CH2Cl2 (1L), and 1% MeOH in CH2Cl2 (9L)).Product-containing fractions are combined and condensed to afford 3.6 g(54%) of the desired product as a white solid.

Physical characteristics are as follows: m.p. 242-244° C.; 1H NMR (300MHz, DMSO-d6) δ 10.21, 8.76, 8.44, 8.33, 7.40, 5.48, 4.59, 4.56, 4.39;IR (drift) 1658, 1599, 1579, 1551, 1492, 1457, 1359, 1120, 1114, 1091,1017, 806, 740, 693, 672 cm−1; MS (ESI) for m/z 482.9 (M+H)+; Anal calcdfor C19H16ClIN2O3: C, 47.28; H, 3.34; N, 5.80. Found: C, 47.42; H, 3.36;N, 5.77.

Preparation 14N-(4-chlorobenzyl)-6-(chloromethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide

A solution ofN-(4-chlorobenzyl)-6-(hydroxymethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide(4.89 g), DMAP (209 mg) and collidine (1.59 mL) in 173 mL anhydrous DMFis heated to 65° C. to solubilize the starting material. To thissolution is added methanesulfonyl chloride (2.77 mL) at roomtemperature. The reaction is heated at 65° C. for 2 h, then allowed tocool to room temperature. The reaction is poured into H2O (300 mL) toprecipitate the product. The solid is filtered and recrystallized fromCH2Cl2/hexanes to afford 4.74 g (93%) of the desired product as a whitesolid.

Physical characteristics are as follows: m.p. 237-239° C.; 1H NMR (300MHz, DMSO-d6) δ 10.14, 8.78, 8.57, 8.43, 7.38, 4.91, 4.56, 4.40; IR(drift) 3051, 1661, 1599, 1577, 1552, 1491, 1401, 1357, 1261, 1115,1106, 1092, 807, 799, 710 cm−1; MS (ESI) for m/z 500.7 (M+H)+; Analcalcd for C19H15Cl2IN2O2: C, 45.54; H, 3.02; N, 5.59. Found: C, 45.50;H, 3.05; N, 5.58.

Preparation 15N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide

A solution ofN-(4-chlorobenzyl)-6-(chloromethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide(3.95 g), N,N-diisopropylethylamine (1.79 mL), and morpholine (0.96 mL)in anhydrous DMF (149 mL) is heated at 65° C. for 1-2 h. The reaction isallowed to cool to room temperature, then poured into H2O (300 mL) toprecipitate the product. The solid is filtered, adsorbed onto silica,and chromatographed (eluent 100% CH2Cl2 (0.5% CH2Cl2 (1L), 1% MeOH inCH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1 L), 2% MeOH in CH2Cl2 (1L), 2.5%MeOH in CH2Cl2 (2L)). Product-containing fractions are combined andcondensed to afford 3.17 g (73%) of the desired product as a whitesolid.

Physical characteristics are as follows: m.p. 156-158° C.; 1H NMR (300MHz, DMSO-d6) δ 10.19, 8.77, 8.45, 8.30, 7.38, 4.55, 4.39, 3.58, 2.37;IR (drift) 1662, 1598, 1575, 1544, 1489, 1458, 1398,1360, 1347, 1333,1243, 1114, 1015, 1008, 810 cm−1; MS (FAB) m/z 552, 554, 553, 552, 551,550, 426, 425, 411, 125, 100; Anal calcd for C23H23ClIN3O3: C, 50.06; H,4.20; N, 7.61. Found: C, 49.99; H, 4.15; N, 7.58.

Example 4N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide

To a solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(264 mg), PdCl2(PPh3)2 (17.3 mg), and CuI (4.7 mg) in 9.6 mL Et2NH isadded propargyl alcohol (0.029 mL, 0.492 mmol). Distilled CH2Cl2 (14 mL)is added to help solublize the reactants. The reaction is stirred atroom temperature overnight, then condensed to remove the solvents. Thecrude product is adsorbed onto silica and chromatographed (eluent 1%MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), and 3% MeOH in CH2Cl2(2L)). Product-containing fractions are combined and condensed to afford148.2 mg (63%) of the desired product as a tan solid.

Physical characteristics are as follows: m.p. 180-183° C.; 1H NMR (300MHz, DMSO-d6) δ 10.27, 8.76, 8.28, 7.85, 7.38, 5.43, 4.56; 4.43, 4.39,3.58; 2.37; IR (drift) 3415, 3364, 1662, 1602, 1578, 1551, 1492, 1432,1361, 1352, 1330, 1114, 1017, 810, 799 cm−1; HRMS (FAB) calcd forC26H26ClN3O4+H1 480.1690, found 480.1697.

Example 5N-(4-chlorobenzyl)-8-[3-(dimethylamino)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide

To a solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(300 mg), PdCl2 (PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) isadded 1-dimethylamino-2-propyne (0.065 mL). Anhydrous DMF (10 mL) isadded to help solubilize the reactants (also requires sonication). Thereaction is stirred at room temperature overnight, then condensed. Theresulting residue is placed under high vac to remove residual DMF. Thecrude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 andH2O. The aqueous layer is extracted with CH2Cl2 (2×). The combinedorganic layers are dried over Na2SO4, filtered, and condensed. The crudeproduct is adsorbed onto silica and chromatographed (eluent 1% MeOH inCH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), 3% MeOH in CH2Cl2 (1L), 5% MeOH inCH2Cl2 (1L), and 6% MeOH in CH2Cl2 (1L)). Product-containing fractionsare combined, concentrated, and recrystallized from hot acetonitrile toafford 153.5 mg (55%) of the desired product as a white solid.

Physical characteristics are as follows: m.p. 154-157° C.; 1H NMR (300MHz, DMSO-d6) δ 10.27, 8.75, 8.29, 7.88, 7.38, 4.56, 4.44, 3.57, 2.37,2.28; IR (drift) 2938, 2817, 2768, 1653, 1600, 1581, 1555, 1531, 1490,1464, 1361, 1344, 1113, 886, 809 cm−1; Anal. calcd for C28H31ClN4O3: C,66.33; H, 6.16; N, 11.05. Found: C, 66.07; H, 6.17; N, 11.04.

Example 6N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide

To a solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) isadded 1-dimethylamino-2-propyne (0.065 mL). Anhydrous DMF (10 mL) isadded to help solubilize the reactants (also requires sonication). Thereaction is stirred at room temperature overnight, then condensed. Theresulting residue is placed under high vac to remove residual DMF. Thecrude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 andH2O. The aqueous layer is extracted with CH2Cl2 (2×). The combinedorganic layers are dried over Na2SO4, filtered, and condensed. The crudeproduct is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2(1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH inCH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), and 2.5% MeOH in CH2Cl2 (3L)).Product-containing fractions are combined, concentrated, andrecrystallized from hot acetonitrile to afford 125.6 mg (47%) of thedesired product as a white solid.

Physical characteristics are as follows: m.p. 168-170° C.; 1H NMR (300MHz, DMSO-d6) δ 10.29, 8.74, 8.25, 7.83; 7.38, 4.97, 4.55, 4.44, 3.64,3.57, 2.65, 2.36; IR (drift) 1657, 1603, 1557, 1492, 1459, 1397, 1361,1351, 1126, 1108, 1055, 1039, 859, 809, 794 cm−1; HRMS (FAB) calcd forC27H28ClN3O4+H1 494.1846, found 494.1838.

Example 7N-(4-chlorobenzyl)-8-[(3S)-3-hydroxy-1-butynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide

To a solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) isadded (R)-(+)-3-butyn-2-ol (0.047 mL, 0.599 mmol). Anhydrous DMF (10 mL)is added to help solubilize the reactants (also requires sonication).The reaction is stirred at room temperature overnight, then condensed.The resulting residue is placed under high vac to remove residual DMF.The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combinedorganic layers are dried over Na2SO4, filtered, and condensed. The crudeproduct is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2(1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH inCH2Cl2 (1L), and 2% MeOH in CH2Cl2 (4L)). Product-containing fractionsare combined, concentrated, and recrystallized from hot acetonitrile toafford 90.7 mg (34%) of the desired product as a white solid.

Physical characteristics are as follows: m.p. 158-161° C.; 1H NMR (300MHz, DMSO-d6) δ 10.28, 8.75, 8.27, 7.82, 7.38, 5.58, 4.67, 4.56, 4.42,3.57, 2.37, 1.42; IR (drift) 2959, 2927, 2860, 2815, 1656, 1604, 1555,1493, 1457, 1409, 1359, 1347, 1322, 1112, 810 cm−1; Specific Rotation(25° C.) αD=16 (c 0.92, DMSO); Anal calcd for C27H28ClN3O4: C, 65.65; H,5.71; N, 8.51. Found: C, 65.33; H, 5.75; N, 8.53.

Example 8N-(4-chlorobenzyl)-8-[(3R)-3-hydroxy-1-butynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide

To a solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) isadded (S)-(−)-3-butyn-2-ol (0.047 mL). Anhydrous DMF (20 mL) is added tohelp solubilize the reactants (also requires sonication). Reaction isstirred at room temperature overnight, then condensed. The resultingresidue is placed under high vac to remove residual DMF. The crudeproduct is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O.The aqueous layer is extracted with CH2Cl2 (2×). The combined organiclayers are dried over Na2SO4, filtered, and condensed. The crude productis adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L),0.5% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2(1L), and 2.5% MeOH in CH2Cl2 (2L)). Product-containing fractions arecombined, concentrated, and recrystallized from hot acetonitrile toafford 108.8 mg (41%) of the desired solid as a white solid.

Physical characteristics are as follows: m.p. 147-150° C.; 1H NMR (400MHz, DMSO-d6) δ 10.28, 8.75, 8.28, 7.83, 7.38, 5.58, 4.67, 4.56, 4.42,3.58, 2.37, 1.42; IR (drift) 3314, 2972, 2931, 1653, 1604, 1569, 1551,1493, 1411, 1361, 1350, 1281, 1113, 810, 796 cm−1; MS (ESI) for m/z494.0 (M+H)+; Specific Rotation (25° C.) αD=−18 (c 0.89, DMSO); Analcalcd for C27H28ClN3O4: C, 65.65; H, 5.71; N, 8.51. Found: C, 66.03; H,6.03; N, 8.19.

Example 9N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-8-{4-[(4R)-2-oxo-1,3-oxazolidin-4-yl]-1-butynyl}-1,4-dihydro-3-quinolinecarboxamide

To a solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) isadded (4R)-4-(3-butynyl)-1,3-oxazolidin-2-one (83.4 mg). Anhydrous DMF(20 mL) is added to help solubilize the reactants (also requiressonication). The reaction is stirred at room temperature overnight, thencondensed. The resulting residue is placed under high vac to removeresidual DMF. The crude product is dissolved in CH2Cl2 and partitionedbetween CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×).The combined organic layers are dried over Na2SO4, filtered, andcondensed. The crude product is adsorbed onto silica and chromatographed(eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2(1L), 1.5% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), and 2.5% MeOH inCH2Cl2 (3L)). Product-containing fractions are combined, concentrated,and recrystallized from hot acetonitrile to afford 95.6 mg (31%) of thedesired product as a white solid.

Physical characteristics are as follows: m.p. 171-173° C.; 1H NMR (300MHz, DMSO-d6) δ 10.28, 8.75, 8.26, 7.92, 7.83, 7.38, 4.55, 4.42, 4.02,3.92, 3.57, 2.58, 2.36, 1.79; IR (drift) 3218, 1755, 1736, 1655, 1601,1569, 1551, 1535, 1492, 1361, 1346, 1246, 1114, 807, 798 cm−1; HRMS(FAB) calcd for C30H31ClN4O5+H1 563.2061, found 563.2055; SpecificRotation (25° C.) αD=25 (c 0.96, DMSO).

Example 10N-(4-chlorobenzyl)-8-(5-hydroxy-1-pentynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide

To a solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(300 mg), PdCl2 (PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) isadded 4-pentyn-1-ol (0.056 mL). Anhydrous DMF (20 mL) is added to helpsolubilize the reactants (also requires sonication). The reaction isstirred at room temperature overnight, then condensed. The resultingresidue is placed under high vac to remove residual DMF. The crudeproduct is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O.The aqueous layer is extracted with CH2Cl2 (2×). The combined organiclayers are dried over Na2SO4, filtered, and condensed. The crude productis adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L),0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2(1L), and 2% MeOH in CH2Cl2 (5L)). Product-containing fractions arecombined, concentrated, and recrystallized from hot acetonitrile toafford 117.5 mg (43%) of the desired product as a creme solid.

Physical characteristics are as follows: m.p. 179-182° C.; 1H NMR (300MHz, DMSO-d6) δ 10.28, 8.74, 8.25, 7.82, 7.38, 4.58, 4.42, 3.57, 3.53,2.57, 2.37, 1.73; IR (drift) 3042, 2958, 2931, 2861, 2849, 2817, 1656,1602, 1551, 1491, 1361, 1348, 1118, 809, 798 cm−1; MS (ESI) for m/z508.0 (M+H)+, 506.0 (M−H)−; Anal calcd for C28H30ClN3O4: C, 66.20; H,5.95; N, 8.27. Found: C, 66.23; H, 6.08; N, 8.11.

Example 11N-(4-chlorobenzyl)-8-[3-(1,1-dioxido-4-thiomorpholinyl)-1-propynyl]-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide

To a solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) isadded 4-propargylthiomorpholine-1,1-dioxide (103.8 mg). Anhydrous DMF(18 mL) is added to help solubilize the reactants (also requiressonication). The reaction is stirred at room temperature overnight, thencondensed. The resulting residue is placed under high vac to removeresidual DMF. The crude product is dissolved in CH2Cl2 and partitionedbetween CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×).The combined organic layers are dried over Na2SO4, filtered, andcondensed. The crude product is adsorbed onto silica and chromatographed(eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2(1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (4L), and 2.5%MeOH in CH2Cl2 (3L)). Product-containing fractions are combined,concentrated, and further purified by HPLC. The product isrecrystallized from hot acetonitrile to afford 86.1 mg (27%) of thedesired product as a white solid.

Physical characteristics are as follows: m.p. 220-222° C.; 1H NMR (300MHz, DMSO-d6) δ 10.27, 8.76, 8.30, 7.88, 7.38, 4.56, 4.43, 3.81, 3.59,3.18, 3.06, 2.37; IR (drift) 1672, 1608, 1563, 1538, 1491, 1359, 1352,1334, 1310, 1302, 1292, 1273, 1125, 1112, 812 cm−1; MS (ESI) for m/z596.8 (M+H)+, 594.7 (M−H)−; Anal calcd for C30H33ClN4O5S: C, 60.34; H,5.57; N, 9.38. Found: C, 60.15; H, 5.62; N, 9.39.

Example 12N-(4-chlorobenzyl)-8-(3-fluoroprop-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A suspension of propargyl bromide (4.68 mL of an 80 wt % solution intoluene) and KF (12.6 g) in diethylene glycol (19.3 mL) is heated at 56°C. for 5 h in a 100 mL one-necked 14/20 round-bottom flask. This flaskis connected to a bulb-to-bulb distillation apparatus. The receiving endof this apparatus is connected to a 50 mL one-necked 14/20 round-bottomflask containing a solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) andanhydrous DMF (18 mL) cooled to a sub-zero temperature with adry-ice/acetone bath. After 5 h, the dry-ice/acetone is replaced withice water to warm the receiving flask to 0° C. The receiving flask ismaintained at 0-10° C. for 2.5 h, then allowed to stir at roomtemperature for 2 days. The reaction mixture is condensed, then furtherdried under the vacuum pump to remove DMF. The resulting crude solid isdissolved in CH2Cl2 and partitioned against H2O. The layers areseparated. The aqueous layer is washed with CH2Cl2 (2×). Organics arecombined, dried over Na2SO4, filtered, and condensed to afford a solid.The solid is adsorbed onto silica and chromatographed (eluant 1% MeOH inCH2Cl2 (1L)). Product-containing fractions are combined and condensed toafford a solid consisting of the desired product and starting material.The mixture is separated by HPLC and the desired product is furtherpurified by Biotage flash chromatography (eluant 100% CH2Cl2 (1L) and 1%MeOH in CH2Cl2 (1L)). Product-containing fractions are combined,condensed, and recrystallized from hot acetonitrile to afford 65.2 mg ofthe title compound as white needles.

Physical characteristics are as follows: m.p. 189-191° C.; 1H NMR (300MHz, DMSO-d6) δ 10.25, 8.77, 8.34, 7.94, 7.38, 5.52, 5.36, 4.56, 4.41,3.58, 2.38; IR (diffuse reflectance) 3053, 1662, 1604, 1569, 1551, 1493,1459, 1409, 1365, 1347, 1124, 1112, 1008, 985, 811 cm−1; HRMS (FAB)calcd for C26H25ClFN3O3+H1 482.1646, found 482.1650; Anal. Calcd forC26H25ClFN3O3: C, 64.79; H, 5.23; N, 8.72. Found: C, 64.58; H, 5.29; N,8.69.

Example 13N-(4-chlorobenzyl)-8-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

To a suspension ofN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) andanhydrous DMF (10 mL) is added 4,5-dichloro-1-prop-2-ynylimidazole(104.8 mg). The reaction is sonicated and stirred at room temperaturefor 2 days. The reaction is condensed to afford a residue. The residueis adsorbed onto silica and chromatographed (eluant 100% CH2Cl2 (1L),0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2(1L), and 2% MeOH in CH2Cl2 (3L)). Product-containing fractions arecombined and condensed to afford 20 mg of the title compound as a whitesolid.

Physical characteristics are as follows: m.p. 178-181° C.; 1H NMR (300MHz, DMSO-d6) δ 10.24, 8.75, 8.32, 8.01, 7.90, 7.38, 5.31, 4.55, 4.35,3.58, 2.36; IR (diffuse reflectance) 1666, 1608, 1573, 1542, 1491, 1408,1355, 1248, 1114, 977, 863, 848, 810, 802, 652 cm−1; MS (FAB) m/z 598,602, 601, 600, 599, 598, 597, 596, 150, 125, 100; Anal. calcd forC29H26Cl3N5O3: C, 58.16; H, 4.38; N, 11.69. Found: C, 58.22; H, 4.49; N,11.49.

Example 14N-(4-chlorobenzyl)-1-methyl-8-[3-(5-methyl-1H-imidazol-1-yl)prop-1-ynyl]-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

To a solution ofN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) isadded 5-methyl-1-prop-2-ynyl-1H-imidazole hydrobromide (120.4 mg).Anhydrous DMF (10 mL) is added to help solubilize the reactants (alsorequires sonication). The reaction is stirred at room temperatureovernight, then condensed. The resulting residue is placed under highvacuum to remove residual DMF. The crude product is dissolved in CH2Cl2and partitioned between CH2Cl2 and saturated NaHCO3. The layers areseparated. The aqueous layer is extracted with CH2Cl2 (2×). The combinedorganic layers are dried over Na2SO4, filtered, and condensed. The crudeproduct is adsorbed onto silica and chromatographed (eluant 1% MeOH inCH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), 3% MeOH in CH2Cl2 (1L), 4% MeOH inCH2Cl2 (2L), and 6% MeOH in CH2Cl2 (1L)). Product-containing fractionsare combined and concentrated to afford a residue. The residue isrecrystallized from hot acetonitrile to afford 87.7 mg of the titlecompound as a tan solid.

Physical characteristics are as follows: m.p. 149-152° C.; 1H NMR (300MHz, DMSO-d6) δ 10.25, 8.74, 8.30, 7.87, 7.71, 7.37, 6.72, 5.20, 4.55,4.32, 3.57, 2.36, 2.29.

Example 15N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-2-ylethynyl)-1,4-dihydroquinoline-3-carboxamide

A flame-dried flask under an atmosphere of nitrogen gas containingN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(Preparation # 15) (0.28 g) is treated with copper (I) iodide (0.01 g),dichlorobis(triphenylphosphine)palladium (II) (0.03 g),dimethylformamide (DMF) (3 mL) and diethylamine (3 mL). The resultingstirring suspension is treated with 2-ethynylpyridine (0.1 mL). Afterstirring overnight, the suspension is concentrated under reducedpressure and then in vacuo. The residue is adsorbed onto silica gel andis flash column chromatographed on silica eluting with 2% to 6% methanolin dichloromethane. The product-containing fractions are combined andconcentrated under reduced pressure. The resulting material iscrystallized from a mixture of methanol:acetonitrile to afford the titlecompound (0.22 g) as a white solid.

Physical characteristics are as follows: m.p. 234-236° C.; 1H NMR(d6-DMSO) δ 10.3, 8.8, 8.7, 8.4, 8.1, 7.9, 7.7, 7.5, 7.4, 4.6, 3.6, 2.4;HRMS (FAB) calc'd for C30H27ClN4O3+H1 527.1850, found 527.1858; anal.calc'd for C30H27ClN4O3: C, 68.37; H, 5.16; N, 10.63; found: C, 68.14;H, 5.17; N, 10.53.

Example 16N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-3-ylethynyl)-1,4-dihydroquinoline-3-carboxamide

A flame-dried flask under an atmosphere of nitrogen gas containingN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(Preparation # 15) (0.28 g) is treated with copper (I) iodide (0.01 g),dichlorobis(triphenylphosphine)palladium (II) (0.03 g) and3-ethynylpyridine (0.10 g). The solids are treated withdimethylformamide (DMF) (3 mL) and diethylamine (3 mL). The resultingsuspension is stirred for 2 days and is then concentrated under reducedpressure. The residue is flash column chromatographed on silica elutingwith 2% to 4% methanol in dichloromethane. The product-containingfractions are combined and concentrated under reduced pressure. Theresulting material is crystallized from methanol:acetonitrile to affordthe title compound (0.23 g) as a tan solid.

Physical characteristics are as follows: m.p. 195-197° C.; 1H NMR(d6-DMSO) δ 10.3, 8.8, 8.8, 8.6, 8.3, 8.1, 8.0, 7.5, 7.4, 4.6, 4.5, 3.6,2.4; HRMS (FAB) calc'd for C30H27ClN4O3+H1 527.1850, found 527.1851;anal. calc'd for C30H27ClN4O3: C, 68.37; H, 5.16; N, 10.63; found: C,67.99; H, 5.20; N, 10.53.

Example 17N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-8-(pyridin-4-ylethynyl)-1,4-dihydroquinoline-3-carboxamide

A flame-dried flask under an atmosphere of nitrogen gas containingN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(Preparation # 15) (0.28 g) is treated with copper (I) iodide (0.01 g),dichlorobis(triphenylphosphine)palladium (II) (0.03 g) and3-ethynylpyridine (0.10 g). The solids are treated withdimethylformamide (DMF) (3 mL) and diethylamine (3 mL). The resultingsuspension is stirred overnight, concentrated under reduced pressure andfinally in vacuo. The residue is flash column chromatographed on silicaeluting with 2% to 6% methanol in dichloromethane. Theproduct-containing fractions are combined and concentrated under reducedpressure. The resulting material is crystallized from acetonitrile toafford the title compound (0.23 g) as light yellow needles.

Physical characteristics are as follows: m.p. 200-202° C.; 1H NMR(d6-DMSO) δ 10.3, 8.8, 8.7, 8.4, 8.1, 7.6, 7.4, 4.6, 4.5, 3.6, 2.4; HRMS(FAB) calc'd for C30H27ClN4O3+H1 527.1850, found 527.1838; anal. calc'dfor C30H27ClN4O3: C, 68.37; H, 5.16; N, 10.63; found: C, 68.08; H, 5.15;N, 10.54.

Example 18N-(4-chlorobenzyl)-8-(4-hydroxypent-1-ynyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A flame-dried flask under an atmosphere of nitrogen gas containingN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(Preparation # 15) (0.55 g) is treated with copper (I) iodide (0.02 g)and dichlorobis(triphenylphosphine)palladium (II) (0.07 g). The solidsare treated with dimethylformamide (DMF) (6 mL) and diethylamine (6 mL).The resulting suspension is treated with 4-pentyn-2-ol (0.2 mL) andstirred for 4 days. The reaction is concentrated under reduced pressureand the residue is partitioned between ethyl acetate and phosphatebuffer (pH=7). The aqueous phase is extracted with dichloromethane:ethylacetate. The combined organic layers are washed with phosphate buffer(pH=7), brine, dried (Na2SO4), filtered and concentrated under reducedpressure. The residue is flash column chromatographed on silica elutingwith 5% to 11% methanol in ethyl acetate. The product-containingfractions are combined and concentrated under reduced pressure. Theresulting material is crystallized from acetonitrile:methanol and thenre-crystallized from toluene to afford the title compound (0.33 g) asoff-white solid.

Physical characteristics are as follows: m.p. 178-180° C.; 1H NMR(d6-DMSO) δ10.3, 8.7, 8.2, 7.8, 7.4, 4.9, 4.5, 4.4, 3.9, 3.6, 2.6, 2.3,1.2; anal. calc'd for C28H30ClN3O4: C, 66.20; H, 5.95; N, 8.27; found:C, 66.06; H, 6.05; N, 8.20.

Example 19N-(4-chlorobenzyl)-8-[3-(4-hydroxypiperidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(0.14 g) in dichloromethane (3 mL) is treated with triphenylphosphine(0.15 g) and carbon tetrabromide (0.18 g). The reaction is stirredovernight. The resulting suspension is treated with additionaltriphenylphosphine (0.03 g) and carbon tetrabromide (0.03 g). After 4hrs, the mixture is adsorbed onto silica, concentrated under reducedpressure and flash column chromatographed eluting with 3% methanol indichloromethane to provide the crude propargylic bromide contaminatedwith triphenylphosphine oxide.

The crude bromide is dissolved in dichloromethane (5 mL) and is treatedwith 4-hydroxypiperidine (0.24 g). After 3 days, the reaction mixture isdiluted ethyl acetate (100 mL) and is washed with pH=7 phosphate buffer(2×50 mL), brine, dried (Na2SO4), filtered and concentrated underreduced pressure. The residue is flash column chromatographed on silicagel eluting with 4% to 20% methanol in dichloromethane. Theproduct-containing fractions are concentrated under reduced pressure andthe resulting residue is crystallized from methanol:acetonitrile toafford the title compound (0.12 g) as a pale yellow solid.

Physical characteristics are as follows: m.p. 180-183° C.; 1H NMR(d6-DMSO) δ10.3, 8.7, 8.3, 7.9, 7.4, 4.6, 4.6, 4.4, 3.6, 3.5, 2.8, 2.4,2.3, 1.8, 1.45; HRMS (FAB) calc'd for C31H35ClN4O4+H1 563.2425, found563.2435; anal. calc'd for C31H35ClN4O4: C, 66.12; H, 6.26; N, 9.95;found: C, 65.76; H, 6.27; N, 9.96.

Example 20N-(4-chlorobenzyl)-8-[3-(3-hydroxypyrrolidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(0.55 g) in dichloromethane (10 mL) is treated with triphenylphosphine(0.62 g) and carbon tetrabromide (0.77 g). After stirring overnight, thereaction mixture is adsorbed onto silica, concentrated under reducedpressure and flash column chromatographed eluting with 1% to 3% methanolin dichloromethane to provide the crude propargylic bromide contaminatedwith triphenylphosphine oxide. Half of the crude bromide is added todichloromethane (5 mL) and is treated with 3-pyrrolidinol (0.21 mL).After 4 days, the reaction mixture is diluted ethylacetate:dichloromethane and is washed with pH=7 phosphate buffer, brine,dried (Na2SO4), filtered and concentrated under reduced pressure. Theresidue is flash column chromatographed on silica gel eluting with 5% to15% methanol in dichloromethane. The product-containing fractions areconcentrated under reduced pressure and the resulting residue iscrystallized from acetonitrile to afford the title compound (0.08 g) asa light yellow solid.

Physical characteristics are as follows: m.p. 144-146° C.; 1H NMR(d6-DMSO) δ 10.3, 8.7, 8.3, 7.9, 7.4, 4.8, 4.5, 4.4, 4.2, 3.7, 3.6, 2.9,2.8, 2.6, 2.5, 2.4, 2.0, 1.6; HRMS (FAB) calc'd for C30H33ClN4O4+H1549.2268, found 549.2252.

Example 21N-(4-chlorobenzyl)-8-{3-[(2,3-dihydroxypropyl)(methyl)amino]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(0.39 g) in dichloromethane (4 mL) is treated with triphenylphosphine(0.42 g) and carbon tetrabromide (0.53 g). After stirring overnight, thereaction mixture is adsorbed onto silica, concentrated under reducedpressure and flash column chromatographed eluting with 2% methanol indichloromethane to provide the crude propargylic bromide contaminatedwith triphenylphosphine oxide. The crude bromide is added todichloromethane (2 mL) and is treated with 3-methylamino-1,2-propanediol(0.16 g). After 2 days, the reaction mixture is added to ethyl acetateand is washed with pH=7 phosphate buffer. The organic phase is treatedwith dichloromethane:methanol and is washed with pH=7 phosphate buffer,brine, dried (Na2SO4), filtered and concentrated under reduced pressure.The residue is flash column chromatographed on silica gel eluting with5% to 20% methanol in dichloromethane. The product-containing fractionsare concentrated under reduced pressure and the resulting residue iscrystallized from acetonitrile to afford the title compound (0.08 g) asa light yellow solid.

Physical characteristics are as follows: m.p. 140-142° C.; 1H NMR(d6-DMSO) δ10.3, 8.7, 8.3, 7.9, 7.4, 4.6-4.5, 4.4, 3.7, 3.6, 2.5, 2.4;HRMS (FAB) calc'd for C30H35ClN4O5+H1 567.2374, found 567.2369

Example 22N-(4-chlorobenzyl)-8-{3-[(2-hydroxyethyl)(methyl)amino]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(0.24 g) in dichloromethane (4 mL) is treated with polymer boundtriphenylphosphine (3 mmol/g, 0.50 g) and carbon tetrabromide (0.33 g).After shaking overnight, the reaction mixture is filtered and the resinwashed with dichloromethane (3×10 mL). The filtrate is concentratedunder reduced pressure and the resulting residue flash columnchromatographed eluting with 2% methanol in dichloromethane to providethe crude propargylic bromide. The crude bromide is added todichloromethane (4 mL) and is treated with N-methyl ethanolamine (0.03mL) and polymer bound trimethylammonium carbonate (3.5 eq/g, 0.4 g).After shaking overnight, the reaction is treated with polymer boundisocyanate resin (1.25 eq/g, 0.5 g). After 4 days, the reaction mixtureis filtered and the resin is washed with dichloromethane (4×10 mL). Thefiltrates are combined and concentrated under reduced pressure. Theresidue is flash column chromatographed on silica gel eluting with 5% to20% methanol in dichloromethane. The product-containing fractions areconcentrated under reduced pressure and the resulting residue iscrystallized from acetonitrile to afford the title compound (0.09 g) asa light yellow solid.

Physical characteristics are as follows: m.p. 148-149° C.; 1H NMR(d6-DMSO) δ10.3, 8.7, 8.3, 7.9, 7.4, 4.6, 4.5, 4.4, 3.7, 3.6, 3.5, 2.6,2.4, 2.3; HRMS (FAB) calc'd for C29H33ClN4O4+H1 537.2268, found537.2267; anal. calc'd for C29H33ClN4O4: C, 64.86; H, 6.19; N, 10.43;found: C, 64.57; H, 6.16; N, 10.46.

Example 23N-(4-chlorobenzyl)-8-[3-(1H-imidazol-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(0.48 g) in dichloromethane (20 mL) is treated with polymer boundtriphenylphosphine (3 mmol/g, 1.0 g) and carbon tetrabromide (0.65 g).After shaking overnight, the reaction mixture is filtered and the resinwashed with dichloromethane (3×20 mL). The combined filtrate isconcentrated under reduced pressure and in vacuo. The resulting crudebromide is added to dichloromethane (3 mL) and is treated with imidazole(0.11 g). After stirring for 2 days, the reaction is diluted withdichloromethane and washed with pH=7 phosphate buffer, brine, dried(Na2SO4), filtered and concentrated under reduced pressure. The residueis flash column chromatographed on silica gel eluting with 2% to 9%methanol in dichloromethane. The product-containing fractions areconcentrated under reduced pressure and the resulting residue iscrystallized from acetonitrile to afford the title compound (0.08 g) asa white solid.

Physical characteristics are as follows: m.p. 178-180° C.; 1H NMR(d6-DMSO) δ10.2, 8.7, 8.3, 7.9, 7.8, 7.4, 7.3, 7.0, 5.3, 4.5, 4.3, 3.6,2.3; HRMS (FAB) calc'd for C29H28ClN5O3+H1 530.1959, found 530.1967;anal. calc'd for C29H28ClN5O3: C, 65.72; H, 5.32; N, 13.21; Cl, 6.69;found: C, 65.50; H, 5.41; N, 13.17.

Example 24N-(4-chlorobenzyl)-8-[5-hydroxy-4-(hydroxymethyl)pent-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A flame-dried flask under an atmosphere of nitrogen gas containingN-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(Preparation # 15) (0.55 g) is treated with2,2,10,10-tetramethyl-3,3,9,9-tetraphenyl-6-prop-2-ynyl-4,8-dioxa-3,9-disilaundecane(Bioorg. Med. Chem. Lett. 1996, 467) (1.4 g), copper (I) iodide (0.02 g)and dichlorobis(triphenylphosphine)palladium (II) (0.07 g). The solidsare treated with dimethylformamide (DMF) (10 mL) and diethylamine (10mL). The resulting suspension is stirred for 4 days and thenconcentrated under reduced pressure. The residue is partitioned betweendichloromethane and phosphate buffer (pH=7). The organic layer is washedwith brine, dried (Na2SO4), filtered and concentrated under reducedpressure. The residue is flash column chromatographed on silica elutingwith 2% to 4% methanol in dichloromethane. The product-containingfractions are combined and concentrated under reduced pressure to affordthe protected diol (0.80 g) as a tan foam. The foam is added as asolution in diethyl ether (10 mL) to a flame-dried flask under anatmosphere of nitrogen gas containing a mixture of acetyl chloride (1.0mL) in methanol (30 mL) at 0° C. After slowly warming to roomtemperature over 4 hours, the reaction mixture is slowly poured intovigorously stirred dichloromethane (50 mL) containing sodium bicarbonate(10 g). After about 10 minutes, the reaction is filtered and the filtercake is washed repeatedly with dichloromethane. The combined filtrate isconcentrated under reduced pressure. The residue is flash columnchromatographed on silica eluting with 2% to 12% methanol indichloromethane. The product-containing fractions are combined andconcentrated under reduced pressure. The residue is crystallized frommethanol:acetonitrile to afford the title compound (0.08 g) as a whitesolid.

Physical characteristics are as follows: m.p. 190-193° C.; 1H NMR(d6-DMSO) δ10.3, 8.7, 8.3, 7.8, 7.4, 4.6, 4.4, 3.6, 3.5, 2.6, 2.4, 1.9;HRMS (FAB) calc'd for C29H32ClN3O5+H1 538.2108, found 538.2114; anal.calc'd for C29H32ClN3O5: C, 64.74; H, 5.99; N, 7.81; found: C, 64.41; H,6.05; N, 7.87.

Example 25N-(4-chlorobenzyl)-8-{3-[3-(hydroxymethyl)piperidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(0.24 g) and dry lithium chloride (0.10 g) in dichloromethane (10 mL)under a drying tube at 0° C. is treated with triethylamine (0.20 mL) andmesyl chloride (0.10 mL). After slowly warming to room temperatureovernight, the reaction mixture is diluted with dichloromethane, washedwith pH=7 phosphate buffer, brine, dried (Na2SO4), filtered andconcentrated under reduced pressure. The resulting residue is dissolvedin dichloromethane (10 mL). Half of the dichloromethane mixture (5 mL)is treated with 3-piperdininemethanol (0.12 g). After shaking for 4days, the reaction is diluted with dichloromethane (10 mL) and istreated with polymer-bound isocyanate resin (1.25 eq/g, 1.0 g). Aftershaking for 2 days, the reaction is filtered, the resin is washed withdichloromethane (3×20 mL), and the combined filtrates are concentratedunder reduced pressure. The residue is dissolved in dichloromethane andis washed with phosphate buffer (pH=7), brine, dried (Na2SO4), filteredand concentrated under reduced pressure. The residue is crystallizedfrom acetonitrile to afford the title compound as a white solid.

Physical characteristics are as follows: 1H NMR (d6-DMSO) δ10.3, 8.7,8.3, 7.9, 7.4, 4.6, 4.5, 4.4, 3.6, 3.3, 2.9, 2.8, 2.4, 2.2, 1.9, 1.6,1.5, 0.9; HRMS (FAB) calc'd for C32H37ClN4O4+H1 577.2581, found577.2590.

Example 26N-(4-chlorobenzyl)-8-{3-[4-(2-hydroxyethyl)piperazin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(0.24 g) in dichloromethane (10 mL) under a drying tube is treated withtriethylamine (0.10 mL) and mesyl chloride (0.05 mL) at 0° C. Afterslowly warming to room temperature overnight, the reaction mixture istreated with triethylamine (0.05 mL) and mesyl chloride (0.03 mL) andstirred overnight. The reaction mixture is diluted with dichloromethaneand washed with pH=7 phosphate buffer. The aqueous phase is extractedwith dichloromethane and the combined organic layer is washed withbrine, dried (Na2SO4), filtered and concentrated under reduced pressure.The resulting residue is dissolved in dichloromethane (10 mL). Half ofthe dichloromethane mixture (5 mL) is treated with1-(2-hydroxyethyl)piperazine (0.13 mL). After shaking for 5 days, thereaction is diluted with dichloromethane (40 mL) and is partitionedagainst phosphate buffer (pH=7, 20 mL). The aqueous phase is extractedwith dichloromethane (20 mL) and the combined organic layer is washedwith brine, dried (Na2SO4), filtered and concentrated under reducedpressure. The residue is crystallized from acetonitrile to afford thetitle compound as a tan solid.

Physical characteristics are as follows: 1H NMR (d6-DMSO) δ10.3, 8.7,8.3, 7.9, 7.4, 4.6, 4.4, 3.6, 3.5, 2.6, 2.5, 2.4; MS (ESI) for m/z 592(M+H)+.

Example 27N-(4-chlorobenzyl)-8-{3-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(3.11 g) in dichloromethane (50 mL) under a drying tube is treated withtriethylamine (2.0 mL) and mesyl chloride (1.0 mL). After stirring atroom temperature overnight, the reaction mixture is diluted withdichloromethane (100 mL) and partitioned against pH=7 phosphate buffer(100 mL). The aqueous phase is extracted with dichloromethane (50 mL)and the combined organic layer is washed with brine, dried (Na2SO4),filtered and concentrated under reduced pressure. The resulting residue(3.0 g) is treated with dichloromethane (80 mL). An aliquot (2 mL) ofthe dichloromethane mixture is transferred to a vial and treated withL-pyrolinol (0.06 mL). After shaking for 2 days, the reaction is dilutedwith diethyl ether:dichloromethane (4:1, 50 mL) and washed withphosphate buffer (pH=7, 15 mL), brine, dried (Na2SO4), filtered andconcentrated under reduced pressure. The residue is crystallized fromacetonitrile to afford the title compound as a solid.

Physical characteristics are as follows: 1H NMR (d6-DMSO) δ10.3, 8.7,8.3, 7.9, 7.4, 4.6, 4.4, 3.8, 3.6, 3.4, 3.3, 3.0, 2.7, 2.6, 2.4, 1.9,1.7, 1.55; MS (ESI) for m/z 563 (M+H)+.

Example 28N-(4-chlorobenzyl)-8-[3-(3-hydroxypiperidin-1-yl)prop-1-ynyl]-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(3.11 g) in dichloromethane (50 mL) under a drying tube is treated withtriethylamine (2.0 mL) and mesyl chloride (1.0 mL). After stirring atroom temperature overnight, the reaction mixture is diluted withdichloromethane (100 mL) and partitioned against pH=7 phosphate buffer(100 mL). The aqueous phase is extracted with dichloromethane (50 mL)and the combined organic layer is washed with brine, dried (Na2SO4),filtered and concentrated under reduced pressure. The resulting residue(3.0 g) is treated with dichloromethane (80 mL). An aliquot (2 mL) ofthe dichloromethane mixture is transferred to a vial and treated with3-hydroxypiperidine (0.05 g). After shaking for 2 days, the reaction isdiluted with diethyl ether:dichloromethane (4:1, 50 mL) and washed withphosphate buffer (pH=7, 15 mL), brine, dried (Na2SO4), filtered andconcentrated under reduced pressure. The residue is crystallized fromacetonitrile to afford the title compound as a solid.

Physical characteristics are as follows: 1H NMR (d6-DMSO) δ10.3, 8.7,8.3, 7.9, 7.4, 4.7, 4.6, 4.3, 3.6, 3.5, 2.9, 2.75, 2.4, 2.2, 2.1, 1.8,1.7, 1.5, 1.1; MS (ESI) for m/z 563 (M+H)+.

Example 29N-(4-chlorobenzyl)-8-{3-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(3.11 g) in dichloromethane (50 mL) under a drying tube is treated withtriethylamine (2.0 mL) and mesyl chloride (1.0 mL). After stirring atroom temperature overnight, the reaction mixture is diluted withdichloromethane (100 mL) and partitioned against pH=7 phosphate buffer(100 mL). The aqueous phase is extracted with dichloromethane (50 mL)and the combined organic layer is washed with brine, dried (Na2SO4),filtered and concentrated under reduced pressure. The resulting residue(3.0 g) is treated with dichloromethane (80 mL). An aliquot (2 mL) ofthe dichloromethane mixture is transferred to a vial and treated withD-pyrolinol (0.06 mL). After shaking for 2 days, the reaction is dilutedwith diethyl ether:dichloromethane (4:1, 50 mL) and washed withphosphate buffer (pH=7, 15 mL), brine, dried (Na2SO4), filtered andconcentrated under reduced pressure. The residue is crystallized fromacetonitrile to afford the title compound as a solid.

Physical characteristics are as follows: 1H NMR (d6-DMSO) δ10.3, 8.7,8.3, 7.9, 7.4, 4.6, 4.4, 3.8, 3.6, 3.4, 3.0, 2.7, 2.6, 2.4, 1.85, 1.7,1.6; MS (ESI) for m/z 563 (M+H)+.

Example 30N-(4-chlorobenzyl)-8-{3-[2-(2-hydroxyethyl)piperidin-1-yl]prop-1-ynyl}-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(3.11 g) in dichloromethane (50 mL) under a drying tube is treated withtriethylamine (2.0 mL) and mesyl chloride (1.0 mL). After stirring atroom temperature overnight, the reaction mixture is diluted withdichloromethane (100 mL) and partitioned against pH=7 phosphate buffer(100 mL). The aqueous phase is extracted with dichloromethane (50 mL)and the combined organic layer is washed with brine, dried (Na2SO4),filtered and concentrated under reduced pressure. The resulting residue(3.0 g) is treated with dichloromethane (80 mL). An aliquot (2 mL) ofthe dichloromethane mixture is transferred to a vial and treated with2-piperidineethanol (0.07 g). After shaking for 2 days, the reaction istreated with sodium iodide (20 mg). After shaking overnight, thereaction is diluted with acetonitrile (1 mL). After shaking overnight,the reaction is diluted with diethyl ether:dichloromethane (4:1, 50 mL)and washed with phosphate buffer (pH=7, 15 mL), brine, dried (Na2SO4),filtered and concentrated under reduced pressure. The residue iscrystallized from acetonitrile to afford the title compound as a solid.

Physical characteristics are as follows: 1H NMR (d6-DMSO) δ10.3, 8.7,8.3, 7.9, 7.4, 4.6, 4.5, 4.4, 3.8, 3.6, 3.5, 2.8, 2.5, 2.4, 1.8,1.7-1.4, 1.2; MS (ESI) for m/z 591 (M+H)+.

Example 318-{3-[butyl(2-hydroxyethyl)amino]prop-1-ynyl}-N-(4-chlorobenzyl)-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

A mixture ofN-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide(3.11 g) in dichloromethane (50 mL) under a drying tube is treated withtriethylamine (2.0 mL) and mesyl chloride (1.0 mL). After stirring atroom temperature overnight, the reaction mixture is diluted withdichloromethane (100 mL) and partitioned against pH=7 phosphate buffer(100 mL). The aqueous phase is extracted with dichloromethane (50 mL)and the combined organic layer is washed with brine, dried (Na2SO4),filtered and concentrated under reduced pressure. The resulting residue(3.0 g) is treated with dichloromethane (80 mL). An aliquot (2 mL) ofthe dichloromethane mixture is transferred to a vial and treated with2-(butylamino)ethanol (0.07 mL). After shaking for 2 days, the reactionis diluted with diethyl ether:dichloromethane (4:1, 50 mL) and washedwith phosphate buffer (pH=7, 15 mL), brine, dried (Na2SO4), filtered andconcentrated under reduced pressure. The residue is crystallized fromacetonitrile to afford the title compound as a solid.

Physical characteristics are as follows: 1H NMR (d6-DMSO) δ10.3, 8.7,8.3, 7.9, 7.4, 4.6, 4.5, 4.4, 3.7, 3.6, 3.5, 2.6, 2.4, 1.5-1.2, 0.9; MS(ESI) for m/z 579 (M+H)+.

What is claimed is: 1.N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide,or its pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a therapeutically effective amount of compound ofclaim 1 and a pharmaceutically acceptable carrier.
 3. A method oftreating infections by herpesviruses, wherein said herpesviruses isherpes simplex virus types 1, herpes simplex virus types 2, varicellazoster virus, cytomegalovirus, Epstein-Barr virus, human herpes viruses6, human herpes viruses 7 or human herpes viruses, which comprisesadministering to an animal in need thereof a therapeutically effectiveamount of compound of claim
 1. 4. The method of claim 3 wherein saidherpesviruses is human cytomegalovirus.
 5. The method of claim 3 whereinthe compound of claim 1 is administered orally, parenterally ortopically.
 6. The method of claim 3 wherein the compound of claim 1 isin an amount of from about 0.1 to about 300 mg/kg of body weight.
 7. Themethod of claim 3, wherein the compound of claim 1 is in an amount offrom about 1 to about 30 mg/kg of body weight.
 8. The method of claim 3,wherein the animal is mammal.
 9. The method of claim 3, wherein theanimal is human.